The present invention relates to a method for the preparation of the well-known anti-depressant drug citalopram, 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile, methods for the preparation of intermediates used in the preparation of citalopram, and methods for conversion of said intermediates into citalopram.
Citalopram is a well-known antidepressant drug that has now been on the market for some years and has the following structure: 
It is a selective, centrally acting serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitor, accordingly having antidepressant activities. The antidepressant activity of the compound has been reported in several publications, eg. J. Hyttel Prog. Neuro-Psychopharmacol. and Biol. Psychiat. 1982, 6, 277-295 and A. Gravem Acta Psychiatr. Scand. 1987, 75, 478-486. The compound has further been disclosed to show effects in the treatment of dementia and cerebrovascular disorders, EP-A 474580.
Citalopram was first disclosed in DE 2,657,013, corresponding to U.S. Pat. No. 4,136,193. This patent publication describes the preparation of citalopram by one method and outlines a further method, which may be used for preparing citalopram.
According to the process described, the corresponding 1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile is reacted with 3-(N,N-dimethylamino)propyl-chloride in the presence of methylsulfinylmethide as condensing agent. The starting material was prepared from the corresponding 5-bromo derivative by reaction with cuprous cyanide.
According to the method, which is only outlined in general terms, citalopram may be obtained by ring closure of the compound: 
in the presence of a dehydrating agent and subsequent exchange of the 5-bromo group with cuprous cyanide. The starting material of Formula II is obtained from 5-bromophthalide by two successive Grignard reactions, i.e. with 4-fluorophenyl magnesium chloride and N,N-dimethylaminopropyl magnesium chloride, respectively.
A new and surprising method and an intermediate for the preparation of citalopram were described in U.S. Pat. No. 4,650,884, according to which an intermediate of Formula III 
is subjected to a ring closure reaction by dehydration with strong sulfuric acid in order to obtain citalopram. The intermediate of Formula III was prepared from 5-cyanophthalide by two successive Grignard reactions, i.e. with 4-fluorophenyl magnesium halogenide and N,N-dimethylaminopropyl magnesium halogenide, respectively.
Further processes are disclosed in international patent application Nos. WO 98019511, WO 98019512 and WO 98019513. WO 98019512 and WO 98019513 relate to methods wherein a 5-amino-, 5-alkoxycarbonyl- or 5-(sec. aminocarbonyl)phthalide is subjected to two successive Grignard reactions, ring closure and conversion of the resulting 1,3-dihydroisobenzofuran derivative to the corresponding 5-cyano compound, i.e. citalopram. International patent application No. WO 98019511 discloses a process for the manufacture of citalopram wherein a (4-substituted-2-hydroxymethylphenyl-(4-fluorophenyl)methanol compound is subjected to ring closure and the resulting 5-substituted 1-(4-fluorophenyl)-1,3-dihydroisobenzofuran converted to the corresponding 5-cyano derivative, which is alkylated with a (3-dimethylamino)propylhalogenide in order to obtain citalopram.
Finally, methods of preparing the individual enantiomers of citalopram are disclosed in U.S. Pat. No. 4,943,590 from which it also appears that the ring closure of the intermediate of Formula III may be carried out via a labile ester with a base.
It has now, surprisingly, been found that citalopram may be manufactured by a novel favourable and safe procedure using convenient starting materials.
Accordingly, the present invention relates to a novel method for the preparation of citalopram having the Formula I 
comprising:
conversion of a compound of Formula VIII 
wherein Z is halogen,
to a compound of Formula IV 
followed by conversion of the compound of Formula IV into citalopram.
In particular the invention relates to such a method comprising:
i) reaction of the compound of Formula IV with a dehydrating agent and a sulfonamide of the Formula H2Nxe2x80x94SO2xe2x80x94R wherein R is:
a) An optionally substituted NH2, or C1-6 alkyloxy,
b) aryloxy or heteroaryloxy optionally substituted with halogen, C1-4-alkyl, cyano, hydroxy, C1-4-alkoxy, trifluoromethyl, nitro, amino, C1-4-alkylamino or di-C1-4-alkylamino, or
c) aryl or heteroaryl optionally substituted with halogen, C1-4-alkyl, cyano, hydroxy, C1-4-alkoxy, trifluoromethyl, nitro, amino, C1-4-alkylamino or di-C1-4-alkylamino; or
ii) conversion of the compound of Formula IV to the corresponding amide of Formula V 
in which R1 and R2 are independently hydrogen, C1-6 alkyl, C1-6 alkyl substituted with one or more substituents selected from the group comprising aryl and heteroaryl, hydroxy, C1-6-alkoxy, aryloxy, heteroaryloxy, aryl-C1-6-alkoxy, or trisubstituted silyl wherein the substituents are independently C1-6 alkyl, aryl, heteroaryl or aryl-C1-6-alkyl and then reacting the amide of Formula V with a dehydrating agent
thereby obtaining citalopram as the base or a pharmaceutically acceptable salt thereof.
The conversion of the 5-carboxy derivative of Formula IV to the amide of Formula V may be carried out via activated acid derivative of Formula VI: 
wherein R3 is halogen, C1-6 alkoxy,aryloxy, heteroaryloxy, aryl-C1-6-alkoxy, heteroaryl-C1-6-alkoxy, alkylcarbonate, arylcarbonate, alkylcarbamate, arylcarbamate, alkylthiocarbonate, arylthiocarbonate, alkylthiocarbamate, arylthiocarbamate, alkylacyloxy, arylacyloxy, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.
In another aspect, the invention relates to methods for the preparation of the intermediate of Formula IV comprising conversion of a compound of Formula VIII, wherein Z is halogen to compound of Formula IV.
In yet another aspect, the invention relates to methods for the preparation of the intermediate of Formula VII 
wherein X is selected from halide, CN, OR5 or SR6 where R5 and R6 are independently selected from C1-6 alkyl, aryl, heteroaryl or benzyl and each of these C1-6 alkyl, aryl, heteroaryl or benzyl groups are unsubstituted or substituted with halogen, C1-4 alkyl, cyano, hydroxy, C1-4 alkoxy, trifluoromethyl, nitro, amino, C1-4 alkylamino or di-C1-4 alkylamino, NR7R8 where R7 and R8 are independently selected from hydrogen, C1-6 alkyl, aryl, heteroaryl or benzyl and each of these C1-6 alkyl, aryl, heteroaryl or benzyl groups are unsubstituted or substituted with halogen, C1-4 alkyl, cyano, hydroxy, C1-4 alkoxy, trifluoromethyl, nitro, amino, C1-4 alkylamino or di-C1-4 alkylamino;
Y is O, S, or NR9 where R9 is selected from hydrogen, C1-6 alkyl, aryl, heteroaryl or benzyl and each of these C1-6 alkyl, aryl, heteroaryl or benzyl groups are unsubstituted or substituted with halogen, C1-4 alkyl, cyano, hydroxy, C1-4 alkoxy, trifluoromethyl, nitro, amino, C1-4 alkylamino or di-C1-4-alkylamino;
comprising
conversion of a compound of Formula VIII 
wherein Z is halogen,
to a compound of Formula VII.
In yet another aspect, the present invention relates to an antidepressant pharmaceutical composition comprising citalopram as the base or any convenient salt thereof manufactured by the process of the invention.
Throughout the specification and claims, the term xe2x80x98dehydrating agentxe2x80x99 refers to any suitable dehydrating agent, and a person skilled in the art may easily determine the optimal agent. Examples of suitable dehydrating agents are SOCl2, POCl3, PCl5, SOBr2, POBr3, PBr5, SOI2, POI3, PI5, P4O10, oxalylchloride, carbonyldiimidazole and Vilsmeier reagents. Preferably a chloro-containing agent, most preferably SOCl2 or POCl3, is used. Vilsmeier reagents are reagents formed by mixing of N,N-dimethylformamide (DMF) and dehydrating agents, examples of which are DMF/SOCl2 and DMF/POCl3.
Throughout the specification and claims, C1-6 alkyl refers to a branched or unbranched alkyl group having from one to six carbon atoms inclusive, such as methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-2-propyl, 2,2-dimethyl-1-ethyl and 2-methyl-1-propyl. Similarly, C1-4 alkyl refers to such a group having from one to four carbon atoms inclusive and C1-6 alkoxy, C1-4 alkoxy and C1-4 alkylamine designate such groups wherein the alkyl moity is as defined.
Halogen means fluorine, chlorine, bromine or iodine.
In the method i) of the invention, one possible but non-limiting mechanism of the reaction is that the 5-carboxy compound of Formula IV reacts with the dehydration agent in order to form a corresponding activated derivative, which then reacts with the sulfonamide, H2Nxe2x80x94SO2xe2x80x94R, thereby forming citalopram. During the latter reaction, a catalytic amount of an acid may be necessary.
The sulfonamide, H2Nxe2x80x94SO2xe2x80x94R, used in the process is preferably sulfamide, NH2xe2x80x94SO2xe2x80x94NH2.
The optionally substituted NH2 used in the process is preferably tert-butylamine.
The reactions with dehydration agents in the method of the invention are carried out neat or in a suitable solvent, such as sulfolane or acetonitrile. When a solvent is used in the dehydration reaction of ii), a catalytic amount of N,N-dimethylformamide may be needed.
In preferred embodiments of the invention, the methods for preparation of citalopram and/or the compounds of Formula IV or Formula VII comprises:
a) Reaction of the 5-halo analogue of Formula VIII 
wherein Z is halogen,
with Mg or an organolithium compound, e.g. n-BuLi, or with an organometallic complex composed of Mg and/or Mn and/or Li and alkyl or aryl groups and subsequently with CO2, CS2 or a compound of the Formula IX 
wherein A and X are independently selected from halide, CN, OR5 or SR6 where R5 and R6 are independently selected from C1-6 alkyl, aryl, heteroaryl or benzyl and each of these C1-6 alkyl, aryl, heteroaryl or benzyl groups are unsubstituted or substituted with halogen, C1-4 alkyl, cyano, hydroxy, C1-4 alkoxy, trifluoromethyl, nitro, amino, C1-4 alkylamino or di-C1-4 alkylamino, NR7R8 where R7 and R8 are independently selected from hydrogen, C1-6 alkyl, aryl, heteroaryl or benzyl and each of these C1-6 alkyl, aryl, heteroaryl or benzyl groups are unsubstituted or substituted with halogen, C1-4 alkyl, cyano, hydroxy, C1-4 alkoxy, trifluoromethyl, nitro, amino, C1-4 alkylamino or di-C1-4 alkylamino; Y is O, S, or NR9 where R9 is selected from hydrogen, C1-6 alkyl, aryl, heteroaryl or benzyl and each of these C1-6 alkyl, aryl, heteroaryl or benzyl groups are unsubstituted or substituted with halogen, C1-4 alkyl, cyano, hydroxy, C1-4 alkoxy, trifluoromethyl, nitro, amino, C1-4 alkylamino or di-C1-4 alkylamino;
and in the methods for manufacture of citalopram or compounds of Formula IV followed by reaction with water, a hydroxide such as NaOH, or an aqueous solution of an acid;
b) coupling of a compound of Formula VIII 
wherein Z is Br or I with an optionally substituted vinyl or acetylenic group in the presence of a metal catalyst, such as a nickel or palladium based catalyst, followed by oxidation of the vinyl or acetylenic group to carboxy thereby obtaining the compound of Formula IV.
In method a), examples of organometallic complexes are trialkylmagnesates of the Formula (R4)3MgLi, trialkylmangenates of the Formula (R4)3MnLi and mixed magnesium and mangenate complexes of the Formula (R4)3MnMgBr, wherein R4 designates C1-6-alkyl or aryl groups that may be identical or different. Trialkylmagnesate may be prepared in situ from a Grignard reagent R4MgX (X is halogen) and an organolithium, e.g. n-butyllithium. Trialkylmangenate may be generated in situ from MnCl2 and an organolithium e.g. n-butyllithium. (R4)3MnMgBr may be prepared from a Grignard reagent R4MgX and MnCl2. The starting 5-bromo compound of Formula VIII may be obtained as described in U.S. Pat. No. 4,136,193.
In method a), examples of starting materials of Formula IX are: ethyl chloroformate, phenyl chloroformate, benzyl chloroformate, vinyl chloroformate, isobutyl chloroformate, ethyl chlorothiolformate, methyl cyanoformate, carbonyldiimidazole and diethyl carbonate. The starting materials of Formula IX are commercially available or may be prepared by literature methods.
In method b), the nickel based catalyst may be any suitable Ni(0) or Ni(II) containing complex which acts as a catalyst, such as Ni(PPh3)3 and ("sgr"-aryl)-Ni(PPh3)2Cl, and the palladium based catalyst may be any suitable Pd(0) or Pd(II) containing catalyst, such as Pd(PPh3)4, Pd2(dba)3 and Pd(PPh)2Cl2. The oxidation agent may be any suitable agent, such as a peroxide in the presence of a ruthenium catalyst. The starting compounds wherein B is a triflate group may be obtained as described in WO 0013648. Examples of the vinyl or acetylenic groups coupled with the compound of Formula VIII are methyl acrylate, 1-bromobut-1-ene, propyne, trimethyl(prop-1-enyl)stannane, E-1-hexenylboronic acid and prop-1-enyl trifluoromethylsulfonate.
The compound of Formula I may be used as the free base or as a pharmaceutically acceptable acid addition salt thereof. As acid addition salts, such salts formed with organic or inorganic acids may be used. Exemplary of such organic salts are those with maleic, fumaric, benzoic, ascorbic, succinic, oxalic, bismethylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzene sulfonic and theophylline acetic acids, as well as the 8-halotheophyllines, for example 8-bromotheophylline. Exemplary of such inorganic salts are those with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids.
The acid addition salts of the compounds may be prepared by methods known in the art. The base is reacted with either the calculated amount of acid in a water miscible solvent, such as acetone or ethanol, with subsequent isolation of the salt by concentration and cooling, or with an excess of the acid in a water immiscible solvent, such as diethylether, ethylacetate or dichloromethane, with the salt separating spontaneously.
The pharmaceutical compositions of the invention may be administered in any suitable way and in any suitable form, for example orally in the form of tablets, capsules, powders or syrups, or parenterally in the form of usual sterile solutions for injection.
The pharmaceutical Formulations of the invention may be prepared by conventional methods in the art. For example, tablets may be prepared by mixing the active ingredient with ordinary adjuvants and/or diluents and subsequently compressing the mixture in a conventional tabletting maschine. Examples of adjuvants or diluents comprise: Corn starch, potato starch, talcum, magnesium stearate, gelatine, lactose, gums, and the like. Any other adjuvant or additive colourings, aroma, preservatives etc. may be used provided that they are compatible with the active ingredients.
Solutions for injections may be prepared by dissolving the active ingredient and possible additives in a part of the solvent for injection, preferably sterile water, adjusting the solution to the desired volume, sterilising the solution and filling it in suitable ampoules or vials. Any suitable additive conventionally used in the art may be added, such as tonicity agents, preservatives, antioxidants, etc.